What Happened to the Vaccine?

When HIV was first discovered in the early 1980s, scientists were optimistic that a vaccine to prevent infection could be developed in a matter of years. Unfortunately, that optimism was misplaced, and HIV has turned out to be a tricky foe for vaccine researchers.

The Antibody Approach Hits a Snag

At the time of HIV's discovery, it was thought that most vaccines worked by triggering a type of immune response called an antibody response (we now know that T cells and other parts of the immune system also play a role). Antibodies are tiny Y-shaped molecules made by a type of immune system cell called a B cell. The job of antibodies is to float around the bloodstream and glom onto pathogens, disabling them and marking them for destruction. Initial experiments in the laboratory showed that HIV grown in a lab dish could be effectively blocked by antibodies that would attach to HIV's outer protein, called the envelope protein. Scientists designed vaccines based on a molecule on HIV's envelope called gp120 in the hopes that these vaccines would trigger the development of similar antibodies in people, thereby protecting them if they were exposed to HIV.

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But before these vaccines could be tested in clinical trials, researchers realized that HIV adapts itself to life in a lab dish in a way that makes it more vulnerable to antibodies than it is in the human body. HIV taken directly from people could not be blocked by the anti-gp120 antibodies that worked against HIV grown in the lab. One company, VaxGen, that was developing a gp120 vaccine decided to respond to this new information essentially by behaving like a child -- covering its ears and singing "la, la, la" in the hopes of not hearing bad news.

VaxGen took its vaccine, named AIDSVAX, all the way to two huge clinical trials designed to test whether it worked. One trial was conducted mainly in North America and most of the participants were gay men. The second trial took place in Thailand among people at risk for HIV infection because of intravenous drug use.

When the results finally became available in 2003, it turned out that the laboratory studies had been right. There were no differences in the number of people that became HIV infected in the trials whether they received AIDSVAX or a placebo (dummy) vaccination. Shamefully, VaxGen attempted to sift through the results of the North American study and suggest that AIDSVAX had shown some protective effect in people of color; this turned out to be a false claim based on a very small number of nonwhite individuals that had enrolled in the trial.

T Cell Responses Take a Turn

While this may sound disastrous, all was not lost because many other scientists continued to work on different vaccine approaches. Over the past decade or so, it has been found that there is another type of immune response against HIV that might be protective. These immune responses are called T cell responses.

T cells come in two main flavors: CD4 cells (which are monitored in people with HIV as a marker of disease progression) and CD8 cells. CD4 cells act like quarterbacks calling the plays for CD8 cells and B cells. CD8 cells have a vitally important function: They can recognize virus-infected cells in the body and zap them with destructive proteins in order to eliminate them. For this reason, they are also sometimes called cytotoxic T cells (cyto comes from the Greek word for cell) or cytotoxic T-lymphocytes (CTL).

Several lines of evidence suggest that CD4 and CD8 cells targeting HIV can play an important role. In monkeys infected with a close relative of HIV called SIV (simian immunodeficiency virus), viral load increases dramatically if researchers artificially deplete the animals of their CD8 cells. People with HIV who do not develop immune deficiency -- long-term nonprogressors -- have been shown to have highly functional CD4 and CD8 cells that target the virus, and their CD8 cells can rapidly kill HIV-infected cells in a lab dish. People with HIV that progresses in the usual way also have CD4 and CD8 cells targeting HIV -- sometimes very large numbers of them -- but when looked at to see how well they work, it turns out they do a poor job of killing infected cells.

Additionally, CD4 and CD8 cells targeting HIV have been found in individuals -- such as sex workers and the uninfected partners of HIV-positive people -- who have been repeatedly exposed to the virus, but remain uninfected (although it is not yet known if these T cell responses are protecting these individuals, or if they just indicate that exposure to HIV has occurred).

The ALVAC Vaccine

As a result of this evidence, and because of the difficulty of blocking HIV with antibodies, a major focus of vaccine researchers has been on designing vaccines that can induce production of CD4 and CD8 cells targeting HIV. While CD4 cell responses can be triggered quite easily, it turned out to be tough to trigger the development of CD8 cell responses.

For most of the 1990s, the best that researchers could do was induce CD8 cell responses targeting HIV in around 20% of HIV-negative people who received an experimental vaccine called ALVAC. ALVAC is a type of vaccine called a viral vector. It is a harmless version of a bird virus called canarypox that has been altered so that it makes several different HIV proteins when injected into people (the proteins cannot form infectious HIV).

Although most researchers think it'll be necessary to trigger CD8 cell responses in more than 20% of recipients for a vaccine to have any chance of working, ALVAC is now being tested in a large trial in Thailand to see if it can offer any protection against HIV infection. Anyone in the trial who becomes infected will also be monitored to see if receiving the vaccine improves his or her chances of becoming a long-term nonprogressor.

Merck Makes a Breakthrough

The big breakthrough for vaccines aiming to trigger CD8 cell responses came just after the turn of the millennium. Merck & Co. developed a different kind of viral vector vaccine, based on a weakened form of a virus called adenovirus (which in its natural form causes bad colds). This vaccine has been shown to trigger CD4 and CD8 cell responses targeting HIV in the majority (50-70%) of people who receive it. The HIV proteins that the vaccine makes are called gag, pol, and nef. Merck's vaccine is now being tested in a trial involving 3,000 HIV-negative people at risk for HIV infection. The trial got under way in January 2005, and results are expected by 2010 at the latest. As with the ALVAC trial, this study will also evaluate whether the vaccine can completely protect against infection or improve a person's chances of becoming a long-term nonprogressor.

The VRC Weighs In

A very similar vaccine has been designed by government researchers at the Vaccine Research Center (VRC) in Bethesda, which is part of the National Institutes of Health. The VRC approach uses a two-pronged strategy called "prime-boost" vaccination. The first vaccine that is given consists of just of a piece of DNA that can make certain HIV proteins when injected into the muscle. This DNA vaccine can induce anti-HIV CD4 and CD8 cells, but only at very low levels. The VRC then uses an adenovirus-based vaccine like Merck's to boost these CD4 and CD8 cells to much higher levels.

The VRC's vaccine includes more HIV proteins: It has gag, pol, and nef, but also includes envelope proteins from three different HIV subtypes from different parts of the world: subtypes A, B, and C. A trial to test the effectiveness of this vaccine involving 8,500 people is just getting under way; preliminary results may be available by 2011.

Therapeutic Vaccines

All of the T cell-based vaccines mentioned in this article (and several others) are also being studied as potential therapies. The goal of therapeutic vaccination is to improve the effectiveness of anti-HIV immune responses in people that are already infected with the virus. Studies typically vaccinate people while they are receiving antiretroviral drugs, so that anti-HIV T cell responses can develop while viral load is suppressed. ART is then interrupted to figure out if these new immune responses can control HIV better than it was being controlled before.

To date, some studies using ALVAC have shown a limited impact of therapeutic vaccination, while others have shown no effect (or even a detrimental effect in one case). Results from studies using the Merck and VRC vaccines have not yet been presented.

Conclusion

Results from these ongoing trials of T cell-based HIV vaccines will be critical for the future of HIV vaccine research. If some significant evidence of protection -- against either infection or disease progression -- is seen, researchers will be able to try to improve on those results and, depending on the degree of success, submit the results to the FDA for approval of the vaccine.

A vaccine that reduced viral load levels could have a beneficial impact on the spread of HIV infection because people with lower viral loads are less likely to transmit the virus. It would be a challenge, however, to develop educational materials about such partially effective vaccines because recipients would need to be informed that they were not fully protected against HIV. If no hint of an effect emerges from the trials of T cell-based vaccines, vaccine researchers will have to ratchet up efforts to develop antibody-based vaccines or alternative approaches (if any can be discovered).

There is no way of knowing what the outcome of these trials may be; most optimistically, many researchers do feel -- based on results in animal models -- that the vaccines may improve the chance that a vaccine recipient who becomes infected with HIV will become a long-term nonprogressor. More pessimistically, few scientists think that these T cell-based vaccines will offer complete protection against HIV infection, since antibodies are thought to be necessary for this to occur.

If these scientists are correct -- and current evidence strongly suggests they are -- then it is extremely unlikely that a completely protective HIV vaccine will become available in our lifetime. We'll only find out for sure in a few years time, when the results of these trials are in.

For more information, visit the AIDS Vaccine Advocacy Coalition at: avac.org. Their AIDS Vaccine Handbook: Global Perspectives (2nd edition) contains a wealth of detail on all aspects of the search for a vaccine, from the ethics of clinical trials to the need for community activism.

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